IntroductionSeveral important advances regarding the clinical epidemiology of inflammatory bowel disease (IBD) were presented during this year's Digestive Disease Week (DDW) meeting. Among the advanced imaging techniques examined, computed tomography (CT) enterography, chromoendoscopy, and magnetic resonance (MR) colography appear to be the leading technologies, whereas wireless capsule endoscopy appears to be less useful than previously believed. Additionally, genetic linkages in IBD are being discovered or confirmed at a very rapid rate, as highlighted in key discussions during these meeting proceedings. Investigators are also elucidating the natural history of IBD from large, meticulously maintained databases to confirm incidence and surgery rates, associations with other diseases, and risk of complications, such as pouchitis or cancer. As further evident from the focus of key sessions at this year's meeting, cancer surveillance in IBD remains a hotly debated topic with somewhat conflicting studies to sort through.

This clinical overview discusses some of the more key DDW sessions documenting these advances.

Advanced Imaging in IBDThere is mounting evidence that chromoendoscopy is a preferred imaging technique for cancer surveillance in ulcerative colitis. This technique could be improved even further with the addition of confocal laser microscopy. In a randomized clinical trial involving 153 patients with long-standing ulcerative colitis, 80 patients underwent conventional colonoscopic surveillance and 73 underwent chromoendoscopy with confocal endomicroscopy for detection of lesions suspicious for neoplasia.[1] Significantly more neoplastic lesions were found in the chromoendoscopy group (19 vs 4; P = .0007). Compared with conventional histology, confocal endomicroscopy had a sensitivity of 95% and a specificity of 98% for identifying neoplastic lesions Therefore, the study authors concluded that chromoendoscopy, as compared with conventional endoscopy, was able to identify lesions likely to be neoplastic, and that confocal laser microscopy could confirm neoplasia in these lesions in vivo.

Wireless capsule endoscopy is used in clinical practice to diagnose Crohn's disease or as a tool to assess extent and severity of disease. In a study by Esrailian and colleagues[2] presented during these meeting proceedings, 41 experts in IBD were asked to judge the appropriateness of wireless capsule endoscopy in 5 case scenarios. The overwhelming majority of experts (> 83% for each case) deemed wireless capsule technology to be "inappropriate" in cases of (1) suspected Crohn's disease; (2) newly diagnosed Crohn's disease; (3) new perianal fistulas; (4) steroid-refractory stricture in Crohn's disease; and (5) postoperative fibrostenotic Crohn's disease. At the present time, experts seem to agree that wireless capsule endoscopy is not helpful in the diagnosis or management of patients with Crohn's disease. Children may be at higher risk than adults for complications from wireless capsule endoscopy. Indeed, a retrospective review by Moy and colleagues[3] found a 22.5% risk for complications among 32 studies in 31 children. Three patients had capsules that did not pass the pylorus by 8 hours (2 patients needed endoscopic removal) and 4 had capsules that did not pass through the small bowel (3 required surgical removal or bowel resection and 1 required steroid treatment). Thus, it is doubtful that the potential benefits of wireless capsule endoscopy justify the risk in pediatric patients.

The utility of CT enterography was evaluated in 51 patients with Crohn's disease of the small bowel to determine whether the additional information provided by this modality changed clinical management (eg, steroid use choices).[4] Although CT enterography correlated poorly with other radiologic and clinical findings, it did change management in 34 (67%) of the patients. On the basis of the additional findings on CT enterography, steroids were added in the management of 14 patients, and 20 patients had steroid therapy reduced or eliminated. Therefore, such application of technology appears to be promising.

Solem and colleagues[5] compared the sensitivity, specificity, and accuracy of CT enterography, wireless capsule endoscopy, small bowel x-ray, and ileoscopy during colonoscopy in the diagnosis of small bowel Crohn's disease. Forty-two patients with suspected or known Crohn's disease were offered all 4 tests sequentially. CT enterography and ileocolonoscopy had the highest accuracy (86% and 85%, respectively). Small bowel x-ray had an accuracy of 79% due to a relatively low sensitivity (65%), and wireless capsule endoscopy had a low accuracy (67%) due to a poor specificity (53%). On the basis of these results, CT enterography appears likely to improve our current approach to diagnosing Crohn's disease.

MR colonography, without colonic cleansing, has been proposed for use in the pediatric IBD patient. In a study by Falconieri and colleagues,[6] 22 pediatric patients (14 with ulcerative colitis, 2 with Crohn's disease, and 6 normal [controls]) underwent unprepped MR colonography to compare the findings with colonoscopy. Twelve of the 14 patients with ulcerative colitis had thickened bowel wall (abnormal MR colonography) that correlated with the extent of disease. The sensitivity and specificity of this test was 81% and 85%, respectively. Thus, on the basis of these findings, MR colonography, with no radiation exposure and no preparation, has certain advantages over other forms of testing for investigation of colonic involvement in pediatric IBD.

Genetic Susceptibility in IBDSome patients with chronic pouchitis may have undiagnosed Crohn's disease. Pouchitis is a common complication after ileal pouch-anal anastomosis for ulcerative colitis, and innate immune responses targeted against enteric bacteria have a role in its pathogenesis. Meier and colleagues[7] conducted a retrospective study of 97 patients with ileal pouch-anal anastomoses to determine whether genetic polymorphisms in the innate immune receptor toll-like receptor 4 and the IBD susceptibility gene NOD2/CARD15 were associated with pouchitis. The L1007fsinsC mutation in CARD15 was found to be associated with chronic pouchitis -- all patients who harbored this mutation developed pouchitis. No patient with intermittent pouchitis or no pouchitis was found to harbor this mutation. Additionally, the toll-like receptor 4 polymorphisms, a common defect in innate immunity dysfunction, were not associated with pouchitis. The study authors concluded that patients with chronic pouchitis had genetic polymorphisms similar to those found in patients with Crohn's disease, whereas in those without pouchitis, the frequency of these polymorphisms was similar to that reported in ulcerative colitis patients and the general population. Thus, CARD15 mutations, particularly the L1007fsinsC polymorphism, may predispose to the development of chronic pouchitis following ileal pouch-anal anastomosis for ulcerative colitis.

There is a purported linkage with IBD on chromosome 10 near the DLG5 gene (codes for an important scaffolding protein). Cummings and colleagues[8] conducted a case-control study to examine the contribution of variants in this gene to disease heterogeneity in IBD. The study authors compared 699 IBD patients with 360 controls; no associations with DLG5 polymorphisms were found, even when patients were stratified according to CARD15 polymorphisms. In another cohort involving 981 IBD patients and 305 controls, the OCTN (carnitine/organic cation transporter) gene cluster on chromosome 5 (the IBD5 locus) was found to be associated with fistulizing Crohn's disease (odds ratio [OR]: 1.47, 95% confidence interval [CI] 1.03-2.11).[9] No associations with IBD (ie, a particular phenotype) were found for the DLG5 gene.

Studying phenotypic homogeneous subgroups of IBD patients may increase the likelihood of finding genotype-phenotype correlations. In a study involving 867 IBD-affected relative pairs, linkage was found for CARD15 (IBD1 locus) and ileal Crohn's disease (lod score [measure of degree of linkage] = 2.56; P = .035), the IBD2 locus and extensive ulcerative colitis (lod = 3.27; P < .001), Crohn's disease in non-Jewish patients and IBD3 (lod = 2.93 for colonic disease, lod = 2.97 for perianal disease), and evidence for linkage on IBD5 was seen in non-Jewish patients with colonic disease (lod =2.85).[10] Very few of these associations could have been identified without examining homogeneous subgroups.

Blood samples were collected from 595 patients with IBD and 627 controls followed for more than 10 years in the European Cooperative IBD study. Data from this cohort are unique in that they can facilitate the investigation of whether genetic or immune markers influence longitudinal changes in disease phenotypes. Riis and colleagues[11] studied mutations in CARD15 and ASCA (anti-Saccharomyces cerevisiae) with regard to longitudinal changes in disease phenotype among IBD patients The immune marker ASCA and CARD15 were found to be associated with a change in behavior over time from inflammatory to stricturing or fistulizing Crohn's disease (OR: 3.2; 95% CI: 1.2-8.8). Indeed, both genetic factors and abnormal immune responses to bacterial stimuli are believed to play a role in the pathogenesis underlying Crohn's disease. Recently, an association between Crohn's disease and CARD8 located in the IBD6 region (19p13) has been reported. In a study of 354 patients with Crohn's disease and 225 matched controls, the combination of CARD8 mutations in the IBD6 region on chromosome 19 and anti-OmpC (antibody to a protein expressed by Escherichia coli) was found to be synergistically associated with fistulizing Crohn's disease.[12] The study authors theorized that a mutation in the CARD8 protein could lead to a dysregulated immune response that when coupled with an aberrant immune response to commensal bacteria (anti-OmpC mutation) could lead to an aggressive, transmural inflammatory disease.

Natural History of IBDAutoimmune manifestations are reported to be associated with both Crohn's disease and ulcerative colitis. In this context, Bernstein and colleagues[13] assessed the coincident occurrence of IBD and other autoimmune disorders using population-based data from Manitoba. Odds ratios significantly greater than 1 were found for asthma, bronchitis, and psoriasis with Crohn's disease, and for asthma, bronchitis, psoriasis, multiple sclerosis, and chronic renal disease with ulcerative colitis. Asthma was the most common autoimmune disorder found to be coincident with IBD. Thyroiditis and neuropathy were not more common in patients with IBD compared with controls. In a related investigation, Tang and colleagues[14] conducted a retrospective study using the University of Manitoba IBD database to examine fistula formation in patients with Crohn's disease. They found that 19.2% of the Crohn's disease population had fistulas. If perianal fistulas were present, the risk of having a concomitant luminal fistula was found to be significantly increased (OR: 4.45; 95% CI: 2.92-6.76). Therefore, the presence of perianal fistulas should prompt an examination for luminal fistulous disease. In another study reported during these meeting proceedings, Bernstein and colleagues[15] assessed the burden of IBD using population-based data from 5 provinces in Canada. Incidence rates for Crohn's disease per 100,000 ranged between 12.2 and 22.5, and for ulcerative colitis ranged between 8.6 and 21.2. Prevalence of disease per 100,000 persons ranged between 231 and 325 for Crohn's disease, and between 182 and 255 for ulcerative colitis. For all IBD, the female:male ratio ranged from 1.14 to 1.29. Thus, overall, the prevalence of IBD in Canada was found to be 491/100,000 persons; that is, 0.5% of the population has IBD.

Is there an association between early postoperative pouch histology and development of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis? To predict the development of acute or chronic pouchitis, investigators from Toronto took biopsies from the pouch of patients soon after surgery and evaluated 109 patients for a mean of 11.5 years.[16] Early inflammation was found to be a predictor of chronic pouchitis (hazard ratio 7.4; 95% CI: 2.14-24.2). The investigators suggested that such patients should be considered for early prophylactic therapy to prevent development of chronic pouchitis. Early histology did not predict the occurrence of acute pouchitis.

What is the colectomy risk in ulcerative colitis after 10 years? The European Cohort IBD group studied 784 patients with ulcerative colitis for a minimum of 10 years to evaluate colectomy rates.[17] They found that only 7.6% of patients had colectomies. It is interesting to note that northern European countries had much higher colectomy rates than southern European countries. Despite the fact that no information on extent of disease was presented, the purported colectomy rate of 20% to 30% in patients with ulcerative colitis is likely to be a gross overestimate.

Cancer Surveillance in IBDAre older patients with late-onset IBD at risk for colorectal cancer and do they require frequent colonoscopic surveillance? Investigators from the Hines VA Hospital in Hines, Illinois, followed 114 older ulcerative colitis patients with late-onset disease and compared outcomes with a comparable group of 6829 non-IBD controls.[18] The annual incidence of cancer in the ulcerative colitis group was 0.14% compared with 0.11% in controls (P = not significant). On the basis of these findings, the investigators suggested that older patients with late-onset ulcerative colitis should undergo surveillance at the same intervals suggested for those with sporadic disease.

The long-term safety of infliximab, an anti-tumor necrosis factor-alpha monoclonal antibody, is currently under investigation. In a case-control study, Biancone and colleagues[19] evaluated the development of neoplasia in 392 patients with Crohn's disease treated with infliximab compared with matched controls. Nine patients treated with infliximab and 6 controls developed neoplasia (OR: 1.51; P = .60). Among those patients in the infliximab-treated group who developed neoplasia, there was 1 cholangiocarcinoma, 3 breast cancers, 2 skin cancers, 1 laryngeal cancer, and 2 anal canal cancers. Among the controls who developed neoplasia, there was 1 ileal adenocarcinoma, 2 skin cancers, 1 lymphoma, 1 cecal adenocarcinoma, and 1 breast cancer. Thus, the results of this study suggest that infliximab did not significantly increase the risk of neoplasia.

Recent reports have suggested that dysplasia and colorectal cancer may be endoscopically visible in many patients with IBD. Rubin and colleagues[20] conducted a retrospective review of a large registry of patients with ulcerative colitis who underwent surveillance examinations over a 10-year period; 1339 examinations were performed in 622 patients. Sixty-four dysplastic lesions were found in 44 patients during this study interval; 35 of 56 (62.5%) dysplastic lesions were visible to the endoscopist, and 7 of 8 (87.5%) cancers were visible. Visible lesions included polyps or masses, strictures, or irregular mucosa. The sensitivity of visibly (ie, by endoscopy) identifying neoplastic lesions was 79.5%. Chromoendoscopy is likely to increase this sensitivity rate much further by making even more lesions visible.

At present, it remains unclear why some patients with IBD have an increased risk of colorectal neoplasia. Jess and colleagues[21] conducted a nested case-control study to investigate risk factors for colorectal neoplasia in 2 large population-based IBD cohorts; 52 patients with ulcerative colitis and neoplasia were compared with a matched set of controls. Significant risk factors for neoplasia included primary sclerosing cholangitis (OR: 8.7), active disease (OR: 3.1), continuously active disease for more than 1 year (OR: 4.0), sulfasalazine use (OR: 1.13), mesalamine use (OR: 1.22), and a higher cumulative dose of steroids (OR: 1.05). These study findings did not support the accumulating evidence that mesalamine may have chemopreventive effects for neoplasia.

Results of population-based studies have demonstrated a slightly increased mortality rate for patients with Crohn's disease over the last 40 years. Wolters and colleagues[22] presented the results of a study assessing mortality risk in a European cohort of Crohn's disease patients 10 years post diagnosis. In this European cooperative study of 371 incident cases of Crohn's disease followed for at least a decade, there were 37 deaths (SMR [standardized mortality ratio] 1.72; 95% CI: 1.21-2.38). There were 8 deaths from gastrointestinal malignancies vs only 0.86 expected (SMR 8.14; 95% CI: 3.26-16.78). In this cohort, patients with Crohn's disease had an increased mortality risk, especially from gastrointestinal malignancies.

Recent reports have suggested a high risk for progression to high-grade dysplasia or cancer among IBD patients with flat low-grade dysplasia; this has led to more aggressive surgical intervention. Jess and colleagues[23] reported the results of a study to assess the true long-term outcome of colorectal dysplasia in a population-based IBD cohort. Among 691 incident ulcerative colitis cases followed in a cancer surveillance program, there were 9 with dysplasia in flat mucosa, 1 with a dysplasia-associated lesion or mass (DALM), and 23 with adenoma-like masses (ALMs). In patients with ALMs, 3 had recurrent adenomas, 3 developed flat low-grade dysplasia, 2 developed DALMs, and 1 developed multifocal Dukes' C adenocarcinoma. Although these findings did not confirm the previously reported risk for progression in flat dysplastic lesions, they did document ALMs as worrisome lesions in patients with ulcerative colitis.

ConclusionOn the basis of data presented during this year's DDW meeting, and as discussed above, the clinical care of IBD patients may evolve and change. Although findings suggest that CT enterography and MR colography will be used more often to diagnose IBD and its complications; wireless capsule endoscopy has not yet found its place in the care of these patients. Chromoendoscopy is sure to improve outcomes from cancer in IBD, but much additional study is needed regarding treatment recommendations for lesions found with such testing. Last, as investigators continue to identify and confirm genes associated with IBD, the closer clinicians are to finding the cause and cure of IBD.

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